Project Summary: Cancer is a leading cause of death, but recent emergence of immunotherapies including the immune checkpoint inhibitors has offer promising new cancer treatment options. It is also evident that tumor immunity is highly complex and incompletely understood. The better understanding of tumor immune regulation may lead to identification of additional targets for cancer immunomodulatory therapy. In our preliminary studies, we found Dickkopf-2 (DKK2), a protein previously known for its antagonism of the Wnt-?-catenin signaling, as being an inhibitor of natural killer cell activation. Genetic inactivation or antibody-mediated neutralization of DKK2 impedes tumor progression in a mouse genetic intestinal tumor model and syngeneic tumor graft models. The action of DKK2 neutralization on grafted tumor progression depends on immune system, specifically on natural killer (NK) cells, as DKK2 neutralizing antibody loses its effectiveness in the NSG immunodeficient mice and in mice NK1.1+ cells are depleted. DKK2 neutralization increases activation of tumor infiltrated NK cells, accompanied by increases in tumor cell apoptosis. These effects of the antibody can be recapitulated in a co- culture of primary mouse NK cells and tumor cells. Moreover, DKK2 protein can directly inhibit activation of NK cells by IL-15 probably by impairing STAT5 nuclear localization. These preliminary results together suggest a hypothesis that DKK2 may promote tumor formation by inhibiting IL-15 signaling and NK cell activation. In this study we will extend our preliminary studies to further test the hypothesis. The specific aims are: 1) To investigate how DKK2 suppresses NK cell activation. 2) To further characterize the mechanism of action for DKK2 inhibition to impede tumor progression. 3) To further evaluate the therapeutic potentials of DKK2 neutralization in cancer treatment using mouse models.